{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T07:10:57Z","timestamp":1790147457444,"version":"4.0.1"},"reference-count":56,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2017,2,6]],"date-time":"2017-02-06T00:00:00Z","timestamp":1486339200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2017,3]]},"abstract":"Summary<\/jats:title>Objective<\/jats:title>The metabotropic glutamate receptor subtype 2 (mG<\/jats:styled-content>lu2<\/jats:sub>) possesses both orthosteric and allosteric modulatory sites, are expressed in the frontal cortex and limbic structures, and can affect excitatory synaptic transmission. Therefore,mG<\/jats:styled-content>lu2<\/jats:sub>is a potential therapeutic target in the treatment of epilepsy. The present study seeks to evaluate the anticonvulsant potential ofmG<\/jats:styled-content>lu2<\/jats:sub>\u2010acting compounds.<\/jats:p><\/jats:sec>Methods<\/jats:title>The anticonvulsant efficacy of two selectivemG<\/jats:styled-content>lu2<\/jats:sub>\u2010positive allosteric modulators (PAMs) (JNJ<\/jats:styled-content>\u201042153605 andJNJ<\/jats:styled-content>\u201040411813\/ADX<\/jats:styled-content>71149) and onemG<\/jats:styled-content>lu2\/3<\/jats:sub>receptor agonist (LY<\/jats:styled-content>404039) were evaluated alone and in combination with the antiseizure drug levetiracetam (LEV<\/jats:styled-content>) in the mouse 6 Hz model.<\/jats:p><\/jats:sec>Results<\/jats:title>In the 6 Hz (32 mA stimulus intensity) model, median effective dose (ED<\/jats:styled-content>50<\/jats:sub>) values were determined forJNJ<\/jats:styled-content>\u201042153605 (3.8 mg\/kg),JNJ<\/jats:styled-content>\u201040411813 (12.2 mg\/kg), andLY<\/jats:styled-content>404039 (10.9 mg\/kg). At the 44 mA stimulus intensity,ED<\/jats:styled-content>50<\/jats:sub>values were determined forJNJ<\/jats:styled-content>\u201042153605 (5.9 mg\/kg),JNJ<\/jats:styled-content>\u201040411813 (21.0 mg\/kg),LY<\/jats:styled-content>404039 (14.1 mg\/kg), andLEV<\/jats:styled-content>(345 mg\/kg). In addition, subprotective doses of eachmG<\/jats:styled-content>lu2<\/jats:sub>\u2010acting compound, administered in combination with various doses ofLEV<\/jats:styled-content>, were able to shift the 6 Hz 44mA ED<\/jats:styled-content>50<\/jats:sub>forLEV<\/jats:styled-content>by >25\u2010fold. WhenJNJ<\/jats:styled-content>\u201042153605 was administered at varying doses in combination with a single dose ofLEV<\/jats:styled-content>(10 mg\/kg), the potency ofJNJ<\/jats:styled-content>\u201042153605 was increased 3.7\u2010fold. Similarly, when a moderately effective dose ofLEV<\/jats:styled-content>(350 mg\/kg) was administered in combination with varying doses ofJNJ<\/jats:styled-content>\u201040411813, the potency ofJNJ<\/jats:styled-content>\u201040411813 was increased approximately 14\u2010fold. Plasma levels ofJNJ<\/jats:styled-content>\u201040411813 andLEV<\/jats:styled-content>were not different when administered alone or in combination, suggesting that increases in potency are not due to pharmacokinetic effects.<\/jats:p><\/jats:sec>Significance<\/jats:title>These studies suggest a potential positive pharmacodynamic effect ofmG<\/jats:styled-content>lu2<\/jats:sub>\u2010acting compounds in combination withLEV<\/jats:styled-content>. If this effect is translated in a clinical setting, it can support a rational polypharmacy concept in treatment of epilepsy patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.13659","type":"journal-article","created":{"date-parts":[[2017,2,6]],"date-time":"2017-02-06T17:46:46Z","timestamp":1486403206000},"page":"484-493","source":"Crossref","is-referenced-by-count":28,"title":["Efficacy of mGlu2<\/sub>\u2010positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures"],"prefix":"10.1111","volume":"58","author":[{"given":"Cameron S.","family":"Metcalf","sequence":"first","affiliation":[{"name":"NeuroAdjuvants, Inc. Salt Lake City Utah U.S.A."},{"name":"Department of Pharmacology and Toxicology University of Utah Salt Lake City Utah U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian D.","family":"Klein","sequence":"additional","affiliation":[{"name":"NeuroAdjuvants, Inc. Salt Lake City Utah U.S.A."},{"name":"Department of Pharmacology and Toxicology University of Utah Salt Lake City Utah U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misty D.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Utah Salt Lake City Utah U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Pruess","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Utah Salt Lake City Utah U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Ceusters","sequence":"additional","affiliation":[{"name":"Janssen Research and Development Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilde","family":"Lavreysen","sequence":"additional","affiliation":[{"name":"Janssen Research and Development Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Pype","sequence":"additional","affiliation":[{"name":"Janssen Cilag Belgium Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Van Osselaer","sequence":"additional","affiliation":[{"name":"Janssen Research and Development Beerse Belgium"},{"name":"UCB Belgium Anderlecht, Belgium Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy","family":"Twyman","sequence":"additional","affiliation":[{"name":"Janssen Research and Development Titusville New Jersey U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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